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Insulin resistance and hypersecretion in obesity: European Group for the Study of Insulin Resistance (EGIR)
Open accessAbstract
Insulin resistance and insulin hypersecretion are established features of obesity. Their prevalence, however, has only been inferred from plasma insulin concentrations. We measured insulin sensitivity (as the whole-body insulin-mediated glucose uptake) and fasting posthepatic insulin delivery rate (IDR) with the use of the euglycemic insulin clamp technique in a large group of obese subjects in the database of the European Group for the Study of Insulin Resistance (1,146 nondiabetic, normotensive Caucasian men and women aged 18-85 yr, with a body mass index (BMI) ranging from 15 to 55 kg.m-2). Insulin resistance, defined as the lowest decile of insulin sensitivity in the lean subgroup (608 subjects with a mean BMI of 29 kg.m-2). Insulin sensitivity declined linearly with BMI at an age- and sex-adjusted rate of 1.2 micromol.min-1.kg FFM-1 per BMI unit (95% confidence intervals = 1.0-1.4). Insulin hypersecretion, defined as the upper decile of IDR, was significantly (P<0.0001) more prevalent (38%) than insulin resistance in the obese group. In the whole dataset, IDR rose as a function of both BMI and insulin resistance in a nonlinear fashion. Neither the waist circumference nor the waist-to-hip ratio, indices of body fat distribution, was related to insulin sensitivity after adjustment for age, gender, and BMI; both, however, were positively associated (P<0.001) with insulin hypersecretion, particularly in women. In nondiabetic, normotensive obese subjects, the prevalence of insulin resistance is relatively low, and is exceeded by the prevalence of insulin hypersecretion, particularly in women with central obesity. In the obese with preserved insulin sensitivity, risk for diabetes, cardiovascular risk, and response to treatment may be different than in insulin resistant obesity.
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“Because the great majority of glucose disposal after intravenous glucose administration occurs in muscle, these results provide strong evidence that insulin resistance in muscle is the earliest demonstrable defect in the natural history of type 2 diabetes, but that the development of overt type 2 diabetes occurs only in those individuals whose β-cells are unable to compensate for the defect in”
From Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes (2009) · cites this paper as [48]
Experimental — accuracy not yet measuredIn the citing paper
“Given the strong association between BMI and insulin sensitivity (8), groups with large differences in insulin sensitivity are generally difficult to match for BMI and fat mass, complicating data interpretation.”
From Metabolic flexibility to lipid availability during exercise is enhanced in individuals with high insulin sensitivity (2018) · cites this paper as [8]
In the citing paper
“A similar relationship also exists between BMI and the degree of insulin resistance.22”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [22]
In the citing paper
“one study reported that 19, 34 and 60% of individuals with a BMI of <30, ≥30–35 and >35, respectively, were insulin resistant.22”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [22]
In the citing paper
“It is well established that there is a generally directly proportional relationship between BMI and both fasting and postprandial insulin levels.21,22”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [22]
In the citing paper
“The hyperinsulinemia associated with rising BMI is necessary to overcome insulin resistance and maintain normoglycemia.22”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [22]
In the citing paper
“Insulin hypersecretion also becomes more frequent with increasing BMI;24 28, 49 and 80% of individuals with a BMI of <30, >30–35 and >35, respectively, exhibited insulin hypersecretion.22”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [22]
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Insulin Resistance and the Metabolic Syndrome
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BackgroundHyperinsulinemia and Hyperfiltration in Renal Transplantation
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Self-citationLa cintura hipertrigliceridémica
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“Obesos metabólicamente sanos, sin IR ni SM. han desarrollado IR ni SM. La sensibilidad a la in-sulina es normal y no hay alteración de la glucosa, SM; la proporción de obesos metabólicamente nor-males nor-males puede ser del 20% de los obesos 20 .”
Does metabolic syndrome predict significant angiographic coronary artery disease?
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Genetics of common obesity and type 2 diabetes: please forget diseases and study pathogenic traits
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Valoración de la insulinorresistencia en pacientes con síndrome metabólico
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“They show that among insulin-resistant but not insulin-sensitive individuals, those with higher BMI are less glucose-tolerant and have higher insulin.”
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Prevalence of Metabolic Syndrome in Saudi Population
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“In a non-transplant setting, over 70% of persons with over-weight and obesity retain normal insulin sensitivity when assessed via euglycemic insulin clamp [33].”
BackgroundWoolcott, O. O., Richey, J. M., Kabir, M., Chow, R. H.-P., Iyer, M. S., Kirkman, E. L., Stefanovski, D., Lottati, M., Kim, S. P., Harrison, L. N., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0123558 · Cited by 6
“Typically, obesity is associated with hyperinsulinemia and insulin resistance [6].”
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“Obesity is an important risk factor for insulin resistance.(4,5)”
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Self-citationInsulin resistance and metabolic syndrome criteria in lean, normoglycemic college-age subjects
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Metabolic Health in Severely Obese Subjects: A Descriptive Study
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Metabolic Effects of Combined Antihypertensive Treatment in Patients With Essential Hypertension
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“Insulin resistance is not the only mechanism that increases the insulin secretion; stronger signals originating from the central nervous system may also be involved (Ferrannini et al., 1997).”
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“Reactive hypoglycemia is known to stimulate non-esterified fatty acid (NEFA) release and hepatic lipid build-up, processes that contribute to hypertriglyceridemia and HDL suppression (28, 30–33).”
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Diet Composition and Activity Level of at Risk and Metabolically Healthy Obese American Adults
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“9–11 Evidence has shown that more than 20% of obese people have a normal metabolism, which is termed metabolically healthy obesity (MHO), 12–14 and about 10%–25% of people with normal body mass suffer from MetS, which is called metabolically obese normal weight.”
Obstructive sleep apnea: Is it a biomarker of metabolic health in obesity
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“However, not all obese persons develop metabolic complications, and ~25% of obese adults are “metabolically healthy” based on insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp technique (Ferrannini et al., 1997; Brochu et al., 2001).”
BackgroundAnthropometric Features are not Predictive of 72-Hour Fast Duration in Insulinomas
Donegan, D. M., Jakubíková, I., & Vella, A. V. (2017) · Endocrine Practice · doi:10.4158/ep171872.or · Cited by 5
“hydroxybutyrate at fast termination (mmol/L) Median tumor diameter, mm (range) 14 (1- 97) 14 (6-97) 15 (1-90)”
BackgroundInzulinrezisztencia és következményei gyermek- és serdülőkorban
Tobisch, B., Blatniczky, L., Schusterová, I., Kovács, L., & Barkai, L. (2021) · Orvosi Hetilap · doi:10.1556/650.2021.32048 · Cited by 5
Insulin Resistance and the Metabolic Syndrome
Banerji, M. A., Lam, M. L., & Chaiken, R. L. (2017) · Springer eBooks · doi:10.1007/978-3-319-20797-1_34-2 · Cited by 5
Resistência à insulina com a suplementação de creatina em animais de experimentação
Costallat, B. L., Miglioli, L., Silva, P. A. C., Novo, N. F., & Duarte, J. L. G. (2007) · Revista Brasileira de Medicina do Esporte · doi:10.1590/s1517-86922007000100006 · Cited by 5
“Embora tenha sido demonstrado in vivo(16) que a suplementação crônica de creatina leva a hipersecreção de insulina, não foi estudado o fato de a hipersecreção de insulina ao longo prazo poder induzir também resistência à insulina (20), objeto de estudo do presente trabalho.”
Epidemiology and Comorbidities
Mathus-Vliegen, E. M. H., & Dargent, J. (2018) · Springer eBooks · doi:10.1007/978-3-319-90074-2_1 · Cited by 5
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Insulin resistance versus dysregulation—a distinction without a difference
Kellon, E. M. (2024) · Equine Veterinary Education · doi:10.1111/eve.14082 · Cited by 4
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“Overnutrition associated with weight gain can also lead to obesity and insulin resistance (Ferrannini et al. 1997).”
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Kim, A. H., Seo, I., Lee, H. S., & Lee, Y. (2022) · Endocrine Practice · doi:10.1016/j.eprac.2022.03.004 · Cited by 4
Metabolic Syndrome and Insulin resistance: Etiopathegenesis and influencing factors
Al-Mahmood, A. K., Afrin, S., & Hoque, N. (2013) · Bangladesh Journal of Medical Biochemistry · doi:10.3329/bjmb.v4i2.13773 · Cited by 5
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Uncoupling Obesity from Cancer: Bromodomain Co-regulators That Control Inflammatory Networks
Denis, G. V., & Bowen, D. J. (2013) · Springer eBooks · doi:10.1007/978-1-4614-6819-6_3 · Cited by 4
“These un-inflamed subjects exhibit normal or near-normal glucose tolerance [89] (Figure 1), reduced cardiovascular disease risk [16] and lack metabolic syndrome [17, 50, 89].”
BackgroundMetabolic syndrome: the new cardiovascular target
Nestel, P. J. (2004) · Current Opinion in Lipidology · doi:10.1097/00041433-200402000-00002 · Cited by 4
Ordered Stratification to Reduce Heterogeneity in Linkage to Diabetes‐related Quantitative Traits
Meigs, J. B., Manning, A. K., Dupuis, J., Liu, C., Florez, J. C., & Cupples, L. A. (2008) · Obesity · doi:10.1038/oby.2008.354 · Cited by 4
Metabolic syndrome and Framingham risk score in obese young adults
Widjaja, F. F., Widjaja, I. R., Astria, Y., Suwita, C. S., & Waspadji, S. (2013) · Medical Journal of Indonesia · doi:10.13181/mji.v22i2.536 · Cited by 4
Reaven, G. M. (2008) · Cited by 4
Maternal and Paternal Transmission of Diabetes: Influence of Nutritional Factors
Rahim, M. (2015) · Journal of Diabetes & Metabolism · doi:10.4172/2155-6156.1000504 · Cited by 4
Does metabolic syndrome predict significant angiographic coronary artery disease?
Timóteo, A. T., Carmo, M. M., & Ferreira, R. C. (2012) · Revista Portuguesa de Cardiologia (English Edition) · doi:10.1016/j.repce.2012.11.008 · Cited by 4
Bieda, J. (2009) · Deep Blue (University of Michigan) · Cited by 4
Obesity and Disease: Insulin Resistance, Diabetes, Metabolic Syndrome and Polycystic Ovary Syndrome
Proietto, J. (2005) · Wiley eBooks · doi:10.1002/9780470987087.ch13 · Cited by 4
Assessment of Insulin Sensitivity
Szendroedi, J., Phielix, E., & Roden, M. (2011) · Wiley eBooks · doi:10.1002/9781444347319.ch6 · Cited by 4
The Effects of Poor Maternal Nutrition on Postnatal Growth and Development of Lambs
Peck, K. N. (2013) · OpenCommons at University of Connecticut (University of Connecticut) · Cited by 4
Nyamdorj, R. (2010) · Työväentutkimus Vuosikirja · Cited by 4
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“In the circulation, they are rapidly inactivated by dipeptidyl peptidase-4 (DPP-4), which cleaves off two N terminal amino acids [2].”
BackgroundMetabolic effects of bariatric surgery on type 2 diabetes mellitus
Özmen, M. M. (2017) · Laparoscopic Endoscopic Surgical Science · doi:10.14744/less.2014.77486 · Cited by 3
Lee, C. L., Shyam, S., Lee, Z. Y., & Tan, J. L. (2020) · Nutrition and Health · doi:10.1177/0260106020975573 · Cited by 3
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Metadata
- Authors
- Ferrannini, E., Natali, A., Bell, P., Cavallo-Perin, P., Lalic, N., & Mingrone, G.
- Affiliations
- Istituto di Fisiologia Clinica (IT)
- Venue
- Journal of Clinical Investigation
- Published
- 1997-09-01
- Volume
- 100
- Issue
- 5
- Pages
- 1166-1173
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508292
- OpenAlex
- W2036400933
- Cited by
- 898
- References
- 53
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 20 · 2023: 13 · 2022: 20 · 2021: 28 · 2020: 32 · 2019: 26 · 2018: 32 · 2017: 26 · 2016: 26 · 2015: 36 · 2014: 30 · 2013: 36 · 2012: 43
- FWCI
- 10.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Funders
- Università degli Studi di Napoli Federico II
- Helsingin Yliopisto
- Universität Heidelberg
- Lunds Universitet
- Università degli Studi di Padova
- National and Kapodistrian University of Athens
- Université de Genève
- Università degli Studi di Torino
- Università degli Studi di Verona
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- insulin resistance, insulin hypersecretion, obesity, insulin sensitivity, body mass index, waist circumference, waist-to-hip ratio, abdominal obesity, sex differences, hyperinsulinemic-euglycemic clamp, type 2 diabetes risk
- MeSH terms
- Insulin Secretion, Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Obesity, Body Mass Index
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